1. Field of the Invention
This invention relates to a method of preparing pharmaceutically acceptable atorvastatin salts in non-crystalline form.
2. Description of the Related Art
Atorvastatin calcium (USAN: the INN for the salt is atorvastatin), the substance having the chemical name [(R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl-1H-pyrrole-1-heptanoic acid calcium salt (2:1) and the formula 
is known as an HMG-CoA reductase inhibitor and is used as an antihypercholesterolemic agent.
Atorvastatin lactone is the compound of the formula 
Processes for the preparation of atorvastatin and its salts, atorvastatin lactone, and key intermediates, are disclosed in U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952; and 5,397,792. Atorvastatin is usually prepared as the calcium salt since this enables atorvastatin to be conveniently formulated in pharmaceutical formulations, for example, in tablets, capsules, powders and the like for oral administration.
Atorvastatin calcium can exist in amorphous form or in one of several crystalline forms (Form I, Form II, Form III and Form IV), which are disclosed in International Publications Nos. WO 97/3958 (U.S. Pat. No. 6,121,461) and WO 97/3959 (U.S. Pat. No. 5,969,156). It is known that the amorphous forms of a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to the crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38:2003-2007). For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation. Since processes for the crystallization and the preparation, respectively, of the amorphous substance are sometimes difficult, and sometimes afford amorphous-crystalline mixtures, that is, a crystalline form instead of an amorphous form, there is a constant need for processes which enable the preparation of a non-crystalline form without simultaneous formulation of crystalline forms, that is, which will enable the conversion of the crystalline form into the non-crystalline form.
Atorvastatin calcium is a substance which is very slightly water-soluble, and it has been found that the crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin in the body. It has been found that the production of amorphous atorvastatin calcium according to the previously disclosed processes was not consistently reproducible, and therefore a process has been developed for converting the crystalline forms of atorvastatin calcium (formed in the synthesis of atorvastatin) to the amorphous form. The process is described in International Publication No. WO 97/3960 (U.S. Pat. No. 6,087,511) and comprises dissolving a crystalline form of atorvastatin calcium in a non-hydroxylic solvent and removing the solvent to afford amorphous atorvastatin calcium. The preferred non-hydroxylic solvent is selected from the group consisting of tetrahydrofuran and a mixture of tetrahydrofuran and toluene.
The disadvantage of the above process is primarily use of non-nature-friendly solvents. A similar process is described in International Publication No. WO 00/71116 and comprises dissolving the crystalline form of atorvastatin calcium in a non-hydroxylic solvent, such as, for example, tetrahydrofuran. To the solution of atorvastatin calcium is added a nonpolar organic solvent, or the solution of atorvastatin calcium is added to a nonpolar organic solvent, to allow atorvastatin calcium to precipitate. The formed precipitate is filtered off.
Synthesis of amorphous atorvastatin calcium is demanding and accordingly the cost of the finished product is high.
It is an object of this invention to minimize the number of synthesis steps in the process for the preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline form and in this manner to improve the yield.
The present invention provides a process for the conversion of a compound of formula (I) 
where A denotes a common protecting group or separate protecting groups for the two hydroxy groups, and B denotes a carboxylic acid protecting group, into a non-crystalline, in particular amorphous, pharmaceutically acceptable atorvastatin salt, especially the calcium salt, without the need of prior formation of atorvastatin lactone, the crystalline form of the atorvastatin salt, or a mixture of amorphous and crystalline forms of the atorvastatin salt.
In a further aspect, the present invention also provides the conversion of atorvastatin lactone into a non-crystalline, in particular amorphous, pharmaceutically acceptable atorvastatin salt without intermediate formation of the atorvastatin salt in crystalline form or a mixture of amorphous and crystalline forms.
In a still further aspect, the present invention also provides a process for the preparation of a pharmaceutical formulation containing a pharmaceutically acceptable atorvastatin salt, especially the calcium salt, which has been prepared directly in the non-crystalline, in particular in the amorphous, form.